Hormonal derivatives are a class of compounds which plays an important biological role in several essential metabolic transformations. Among said class, thyroid hormones, and particularly, iodinated biphenyl compounds such as, for example, thyroxine ((2S)-2-amine-3-[4-(4-hydroxy-3,5-diiodoxyphenossyl)-3,5-diiodophenyl]propanoic acid), often abbreviated as T4), and triiodothyronine (T3), represent important key molecules, being involved in controlling the rate of various metabolic processes in the body. In particular, the mono-sodium salt of both L-thyroxine and L-triiodothyronine are widely employed in the treatment of several pathologies related to the malfunctioning of thyroid.
A variety of processes for the preparation of T4 and T3 have been disclosed in the past, initially by using animal natural sources as starting material (see U.S. Pat. No. 2,889,363), and later on by enzymatic or bio-mimetic synthesis (see U.S. Pat. No. 2,889,364). A further enhancement has been described in WO 96/11904 (Baxter), where an organometallic oxidative coupling is performed in order to obtain the thyroxine hydrochloride derivative, subsequently converted in the corresponding sodium salt, as appropriate.
IT 1302201 (Bracco) disclosed a process for the synthesis of the mono sodium salt of the L-thyroxine with an improved overall yield compared to a similar process known in the art (see e.g. Chalmers et al., J. Chem. Soc. 1949, 3424). According to the prior art teaching, the preparation of the monosodium salt of L-thyroxine occurs, in the most of the cases, by a proper and controlled acidification of the corresponding disodium salt, substantially as per scheme I, which is identified as FIG. 1.
Typically, the reaction may be carried out by reacting the disodium salt with a strong inorganic acid, for instance hydrochloric acid, followed by a proper pH regulation by using an alkaline base, such as Na2CO3.
In its turn, the disodium salt formerly indicated as compound II may be prepared, for instance, as disclosed in IT 1302201 (Bracco), according to the Scheme II, which is identified as FIG. 2.
As schematically shown above, the 3,5 diiodo thyronine (compound I) is reacted with the widely used KI/I2 system as the iodinating agent of choice (see for instance Taylor et al. The Ohio Journal of Science, Vol. 53, 37-41, 1953), in an aqueous medium and in the presence of a suitable amine.
The so obtained mixture of mono and di-potassium salts (herein general referred as “potassium salt mixture”) is subjected to a subsequent separation and purification steps, including:
(a) the addition of an organic acid;
(b) the separation of the thus obtained “free form” (as a precipitate); and
(c) the final addition of an excess of sodium hydroxide to obtain the L-thyroxine di-sodium salt of formula II.
The applicant has now found a new process whereby compound II can be directly obtained by a conversion of compound I, substantially avoiding the above mentioned supplementary steps (a-c).
In particular, we have now found that by using NaI/I2 in lieu of KI/I2 as iodinating system, the iodination of the 3,5-diiodo thyronine of formula I leads to the L-thyroxine di-sodium salt II, in one step and in high yields and degree of purity. Surprisingly, in fact, and different to the corresponding potassium salt derivative of the prior art, the thus compound II is substantially insoluble in the reaction medium, and it may be promptly collected as such, or even employed as intermediate either in the preparation of the corresponding mono sodium salt or in the preparation of the free form thereof, as described below.